Anogenital tract infections with high-risk human papillomaviruses (HPV) are very common (1-3), causing lesions in, on and/or around the areas of the anus, rectum, penis, vulva, vagina and cervix. Fortunately, the majority of infected subjects clear the infection (4; 5). A persistent infection with a high risk HPV, mostly HPV16, can lead to neoplasia of the anogenital tract, of which cervical intraepithelial neoplasia (CIN) and cervical carcinoma are the most well-known (6; 7). HPV16 infection may also cause a chronic skin disorder of a) the vulva known as vulvar intraepithelial neoplasia (VIN) (8-10), b) the anus called anal intraepithelial neoplasia (AIN), c) the vagina designated as VAIN and d) the penis known as PIN. In contrast to CIN, which in general is effectively treated by eradication of the area involved, these other disease have a chronic nature with high relapse rates after standard treatments (11-13).
The use of immune modifiers, causing inflammatory reactions, have been applied for the treatment of VIN. In particular Imiquimod therapy has been put forward as an alternative approach for the treatment of VIN. Chemically, imiquimod is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. This immune response modifier acts through Toll-like receptor 7 of the innate immune system resulting in the secretion of a multitude of proinflammatory cytokines, among which interferon. There is recent evidence that imiquimod also possesses direct pro-apoptotic activity against tumor cells (14-16). Topical application preserves the anatomy and function of the vulva while surgical excision or ablation of affected skin may be extensive and disfiguring and can carry considerable psychosexual morbidity. Clinical success rates differ and are estimated on 30-87% (17-21).
The HPV16 early antigens E2, E6 and E7 are among the first of proteins that are expressed in HPV-infected epithelia. Previous studies on HPV-specific T-cell immunity against these early antigens showed that type 1 (IFN-γ) T-cell memory against the early antigens can be detected in the majority of healthy sexually active individuals, but is weak or absent in patients with HPV16-induced cervical neoplasia (22-24). In combination with earlier reports that point at a role for CD4+ T-cells in the protection against progressive HPV-infection (reviewed in 25), data argue that CD4+ type 1 T-cell response against the early antigens of HPV16 may play an important role in the protection against progressive HPV16-induced disease.
The goal of the current invention is therefore to provide improved methods and means for the treatment of virally induced intraepithelial neoplasias of the ano-genital tract, such as VIN, CIN, VAIN, PIN and AIN.